Regulation of Microglia and Macrophage Polarization via Apoptosis Signal-Regulating Kinase 1 Silencing after Ischemic/Hypoxic Injury

Inflammation is implicated in ischemic stroke and is involved in abnormal homeostasis. Activation of the immune system leads to breakdown of the blood–brain barrier and, thereby, infiltration of immune cells into the brain. Upon cerebral ischemia, infiltrated macrophages and microglia (resident CNS immune cell) are activated, change their phenotype to M1 or M2 based on the microenvironment, migrate toward damaged tissue, and are involved in repair or damage. Those of M1 phenotype release pro-inflammatory mediators, which are associated with tissue damage, while those of M2 phenotype release anti-inflammatory mediators, which are related to tissue recovery. Moreover, late inflammation continually stimulates immune cell infiltration and leads to brain infarction. Therefore, regulation of M1/M2 phenotypes under persistent inflammatory conditions after cerebral ischemia is important for brain repair. Herein, we focus on apoptosis signal-regulating kinase 1 (ASK1), which is involved in apoptotic cell death, brain infarction, and production of inflammatory mediators after cerebral ischemia. We hypothesized that ASK1 is involved in the polarization of M1/M2 phenotype and the function of microglia and macrophage during the late stage of ischemia/hypoxia. We investigated the effects of ASK1 in mice subjected to middle cerebral artery occlusion and on BV2 microglia and RAW264.7 macrophage cell lines subjected to oxygen-glucose deprivation. Our results showed that ASK1 silencing effectively reduced Iba-1 or CD11b-positive cells in ischemic areas, suppressed pro-inflammatory cytokines, and increased anti-inflammatory mediator levels at 7 days after cerebral ischemia. In cultured microglia and macrophages, ASK1 inhibition, induced by NQDI-1 drug, decreased the expression and release of M1-associated factors and increased those of M2-associated factors after hypoxia/reperfusion (H/R). At the gene level, ASK1 inhibition suppressed M1-associated genes and augmented M2-associated genes. In gap closure assay, ASK1 inhibition reduced the migration rate of microglia and macrophages after H/R. Taken together, our results provide new information that suggests ASK1 controls the polarization of M1/M2 and the function of microglia and macrophage under sustained-inflammatory conditions. Regulation of persistent inflammation via M1/M2 polarization by ASK1 is a novel strategy for repair after ischemic stroke

Comparison of standard versus 90° rotation technique for LMA Flexible™ insertion: a randomized controlled trial

Background Insertion of a flexible laryngeal mask airway (LMA Flexible) is known to be more difficult than that of a conventional laryngeal mask airway. The 90° rotation technique can improve the success rate with a conventional laryngeal mask airway but its effect with the LMA Flexible remains unknown. We assessed whether the 90° rotation technique increased the first-attempt success rate of LMA Flexible insertion versus the standard technique. Methods In total, 129 female patients undergoing breast surgery were analyzed. The primary endpoint was success at the first attempt. The insertion time, number of trials, number of manipulations required, and oropharyngeal leak pressure were also evaluated. Heart rate and mean blood pressure were recorded 1 min before and 1 min after insertion. Blood staining on the LMA Flexible after removal and postoperative sore throat were checked. Results The first-attempt success rates were comparable between the groups (93% vs. 98.3%, P = .20). The insertion time, number of trials and manipulations, hemodynamic variables, and complications, such as blood staining and sore throat, did not differ between the groups. Conclusions The 90° rotation technique is a good alternative to the standard technique for insertion of the LMA Flexible. Trial registration ClinicalTrials.gov(NCT03028896). It was registered retrospectively at Jan 19th, 2017.ASA: American Society of Anesthesiologists; BMI: Body mass index; IV: Intravenous; LMA: Laryngeal mask airway; MAP: Mean arterial pressure; NRS: Numerical rating scale; PACU: Post-anesthetic care unit; SD: Standard deviatio

Mind Bomb 1-Expressing Intermediate Progenitors Generate Notch Signaling to Maintain Radial Glial Cells

SummaryNotch signaling is critical for the stemness of radial glial cells (RGCs) during embryonic neurogenesis. Although Notch-signal-receiving events in RGCs have been well characterized, the signal-sending mechanism by the adjacent cells is poorly understood. Here, we report that conditional inactivation of mind bomb-1 (mib1), an essential component for Notch ligand endocytosis, in mice using the nestin and hGFAP promoters resulted in complete loss of Notch activation, which leads to depletion of RGCs, and premature differentiation into intermediate progenitors (IPs) and finally neurons, which were reverted by the introduction of active Notch1. Interestingly, Mib1 expression is restricted in the migrating IPs and newborn neurons, but not in RGCs. Moreover, sorted Mib1+ IPs and neurons can send the Notch signal to neighboring cells. Our results reveal that not only newborn neurons but also IPs are essential Notch-ligand-presenting cells for maintaining RGC stemness during both symmetric and asymmetric divisions

Identification of Ambient Molecular Clouds Associated with Galactic Supernova Remnant IC443

The Galactic supernova remnant (SNR) IC443 is one of the most studied core-collapse SNRs for its interaction with molecular clouds. However, the ambient molecular clouds with which IC443 is interacting have not been thoroughly studied and remain poorly understood. Using Five College Radio Astronomy Observatory 14m telescope, we obtained fully sampled maps of ~ 1{\deg} \times 1{\deg} region toward IC443 in the 12CO J=1-0 and HCO+ J=1-0 lines. In addition to the previously known molecular clouds in the velocity range v_lsr = -6 to -1 km/s (-3 km/s clouds), our observations reveal two new ambient molecular cloud components: small (~ 1') bright clouds in v_lsr = -8 to -3 km/s (SCs), and diffuse clouds in v_lsr = +3 to +10 km/s (+5 km/s clouds). Our data also reveal the detailed kinematics of the shocked molecular gas in IC443, however the focus of this paper is the physical relationship between the shocked clumps and the ambient cloud components. We find strong evidence that the SCs are associated with the shocked clumps. This is supported by the positional coincidence of the SCs with shocked clumps and other tracers of shocks. Furthermore, the kinematic features of some shocked clumps suggest that these are the ablated material from the SCs upon the impact of the SNR shock. The SCs are interpreted as dense cores of parental molecular clouds that survived the destruction by the pre-supernova evolution of the progenitor star or its nearby stars. We propose that the expanding SNR shock is now impacting some of the remaining cores and the gas is being ablated and accelerated producing the shocked molecular gas. The morphology of the +5 km/s clouds suggests an association with IC443. On the other hand, the -3 km/s clouds show no evidence for interaction.Comment: Accepted for publication in ApJ. 15 pages (with emulateapj.cls), 17 figures, and 2 table

Aggregate Plaque Volume by Coronary Computed Tomography Angiography Is Superior and Incremental to Luminal Narrowing for Diagnosis of Ischemic Lesions of Intermediate Stenosis Severity

ObjectivesThis study examined the performance of percent aggregate plaque volume (%APV), which represents cumulative plaque volume as a function of total vessel volume, by coronary computed tomography angiography (CTA) for identification of ischemic lesions of intermediate stenosis severity.BackgroundCoronary lesions of intermediate stenosis demonstrate significant rates of ischemia. Coronary CTA enables quantification of luminal narrowing and %APV.MethodsWe identified 58 patients with intermediate lesions (30% to 69% diameter stenosis) who underwent invasive angiography and fractional flow reserve. Coronary CTA measures included diameter stenosis, area stenosis, minimal lumen diameter (MLD), minimal lumen area (MLA) and %APV. %APV was defined as the sum of plaque volume divided by the sum of vessel volume from the ostium to the distal portion of the lesion. Fractional flow reserve ≤0.80 was considered diagnostic of lesion-specific ischemia. Area under the receiver operating characteristic curve and net reclassification improvement (NRI) were also evaluated.ResultsTwenty-two of 58 lesions (38%) caused ischemia. Compared with nonischemic lesions, ischemic lesions had smaller MLD (1.3 vs. 1.7 mm, p = 0.01), smaller MLA (2.5 vs. 3.8 mm2, p = 0.01), and greater %APV (48.9% vs. 39.3%, p < 0.0001). Area under the receiver operating characteristic curve was highest for %APV (0.85) compared with diameter stenosis (0.68), area stenosis (0.66), MLD (0.75), or MLA (0.78). Addition of %APV to other measures showed significant reclassification over diameter stenosis (NRI 0.77, p < 0.001), area stenosis (NRI 0.63, p = 0.002), MLD (NRI 0.62, p = 0.001), and MLA (NRI 0.43, p = 0.01).ConclusionsCompared with diameter stenosis, area stenosis, MLD, and MLA, %APV by coronary CTA improves identification, discrimination, and reclassification of ischemic lesions of intermediate stenosis severity

Biological Profiles of Korean Atomic Bomb Survivors in Residence at Daegu and Kyungbuk, Republic of Korea

In 1945, many Koreans, in addition to Japanese, were killed or injured by the atomic bombs dropped on Hiroshima and Nagasaki, Japan. This study compared the biological profiles of Korean atomic bomb survivors in residence at Daegu and Kyungbuk, Republic of Korea with those of a representative sample of Koreans obtained during a similar period. We evaluated anthropometric measurements, blood pressure, blood cell counts, blood chemistry, and urinalysis of survivors (n=414) and age- and sex-matched controls (n=414) recruited from the third Korea National Health and Nutrition Examination Survey conducted in 2005. Univariate analyses revealed significantly higher systolic blood pressure, white blood cell count, and serum total cholesterol, triglycerides, high-density lipoprotein-cholesterol, and aspartate aminotransferase levels (p<0.01) in the survivors. Conversely, hemoglobin concentration, hematocrit, red blood cell count, and the proportion of positive urine occult blood (p<0.01) were lower in the survivors. Our findings suggest that biological profiles of Korean atomic bomb survivors were adversely affected by radiation exposure

Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials

Objective : To assess the efficacy of vitamin and antioxidant supplements in the prevention of cardiovascular diseases. Design : Meta-analysis of randomised controlled trials. Data sources and study selection : PubMed, EMBASE, the Cochrane Library, Scopus, CINAHL, and ClinicalTrials.gov searched in June and November 2012. Two authors independently reviewed and selected eligible randomised controlled trials, based on predetermined selection criteria. Results : Out of 2240 articles retrieved from databases and relevant bibliographies, 50 randomised controlled trials with 294 478 participants (156 663 in intervention groups and 137 815 in control groups) were included in the final analyses. In a fixed effect meta-analysis of the 50 trials, supplementation with vitamins and antioxidants was not associated with reductions in the risk of major cardiovascular events (relative risk 1.00, 95% confidence interval 0.98 to 1.02; I-2=42%). Overall, there was no beneficial effect of these supplements in the subgroup meta-analyses by type of prevention, type of vitamins and antioxidants, type of cardiovascular outcomes, study design, methodological quality, duration of treatment, funding source, provider of supplements, type of control, number of participants in each trial, and supplements given singly or in combination with other supplements. Among the subgroup meta-analyses by type of cardiovascular outcomes, vitamin and antioxidant supplementation was associated with a marginally increased risk of angina pectoris, while low dose vitamin B-6 supplementation was associated with a slightly decreased risk of major cardiovascular events. Those beneficial or harmful effects disappeared in subgroup meta-analysis of high quality randomised controlled trials within each category. Also, even though supplementation with vitamin B-6 was associated with a decreased risk of cardiovascular death in high quality trials, and vitamin E supplementation with a decreased risk of myocardial infarction, those beneficial effects were seen only in randomised controlled trials in which the supplements were supplied by the pharmaceutical industry.Conclusion There is no evidence to support the use of vitamin and antioxidant supplements for prevention of cardiovascular diseases.OAIID:oai:osos.snu.ac.kr:snu2013-01/102/0000052039/7SEQ:7PERF_CD:SNU2013-01EVAL_ITEM_CD:102USER_ID:0000052039ADJUST_YN:YEMP_ID:A077862DEPT_CD:806CITE_RATE:14.093FILENAME:Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease.pdfDEPT_NM:의과학과EMAIL:[email protected]_YN:YCONFIRM:

Myrrh Inhibits LPS-Induced Inflammatory Response and Protects from Cecal Ligation and Puncture-Induced Sepsis

Myrrh has been used as an antibacterial and anti-inflammatory agent. However, effect of myrrh on peritoneal macrophages and clinically relevant models of septic shock, such as cecal ligation and puncture (CLP), is not well understood. Here, we investigated the inhibitory effect and mechanism(s) of myrrh on inflammatory responses. Myrrh inhibited LPS-induced productions of inflammatory mediators such as nitric oxide, prostaglandin E2, and tumor necrosis factor-α but not of interleukin (IL)-1β and IL-6 in peritoneal macrophages. In addition, Myrrh inhibited LPS-induced activation of c-jun NH2-terminal kinase (JNK) but not of extracellular signal-regulated kinase (ERK), p38, and nuclear factor-κB. Administration of Myrrh reduced the CLP-induced mortality and bacterial counts and inhibited inflammatory mediators. Furthermore, administration of Myrrh attenuated CLP-induced liver damages, which were mainly evidenced by decreased infiltration of leukocytes and aspartate aminotransferase/alanine aminotransferase level. Taken together, these results provide the evidence for the anti-inflammatory and antibacterial potential of Myrrh in sepsis